Bone is calcified connective tissue joined to muscle, which has hard and thick calcified surface, carries out the function of supporting body by keeping balance and protects organs. The inner bone marrow is myeloid tissue playing a key role in calcium metabolism. Bone is composed of organic substances such as collagen, osteocalcin and osteonectin, inorganic substances such as calcium, phosphorus and fluorine and water. Bone formation and bone resorption are necessary daily processes in vivo. Bone formation is stimulated by low dose of parathyroid hormone, androgen, estrogen, fluorine, phosphorus, etc and bone resorption is stimulated by physical decompression, agravity, a high dose of parathyroid hormone and adrenocortical steroid, etc. Thus, bone metabolism is regulated by the balance between bone formation and bone resorption.
Osteoporosis is caused by unbalance between bone formation and bone resorption. Precisely, osteoporosis progresses when bone resorption outpaces bone formation. With osteoporosis, calcified bone tissue density decreases and thus compact substance of bone is lost gradually, leading to the expansion of marrow cavity. As symptoms progress, which means bone loss is increasing, fracture occurs frequently even with a minimum impulse. Bone tissue is a dynamic tissue which is designed to carry out repeatedly bone formation by osteoblasts and destroy and bone resorption by osteoclasts.
Bone resorption is processed by osteoclasts and a receptor activator of NF-B receptor (RANKL) is essential for the generation and activation of osteoclasts. RANKL exists in osteoblasts and mesenchymal cells and is bound to a receptor activator of NF-B receptor (RANK) [Hofbauer L. C., Khosla S., Dunstan C. R., Lacey D. L., Boyle W. J., Riggs B. L., The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res., 15(1):2-12, 2000]. Osteoprotegerin (OPG), produced in osteoblasts, acts as a decoy receptor of RANKL to intercept the binding of RANKL and RANK, resulting in the inhibition of differentiation of osteoclast precursors into osteoclasts and activation of osteoclasts [Kong Y. Y., Feige U., Sarosi I., Bolon B., Tafuri A., Morony S., Capparelli C., Li J., Elliott R., McCabe S., Wong T., Campagnuolo G., Moran E., Bogoch E. R., Van G., Nguyen L. T., Ohashi P. S., Lacey D. L., Fish E., Boyle W. J., Penninger J. M.: Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature, 402:304-309, 1999; Suda T., Takahashi N., Udagawa N., Jimi E., Gillespie M. T., Martin T. J.: Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev, 20(3):345-357, 1999; Aubin J. E., Bonnelye E.: Osteoprotegerin and its ligand: a new paradigm for regulation of osteoclastogenesis and bone resorption., Osteoporos Int, 11(11):905-913, 2000].
Osteoporosis is divided into primary and secondary types; primary osteoporosis is exemplified by senile osteoporosis and postmenopausal osteoporosis, and secondary osteoporosis is developed as a complication of hyperthyroidism, hyperparathyroidism, hyperadrenocorticism, pregnancy, prolonged fixation (for example, plaster cast fixation), malnutrition, drugs, cancer or other chronic diseases.
The cause of primary osteoporosis has not been disclosed, yet various factors seem to be involved. It is assumed that osteoporosis is developed by unbalance of bone metabolism by aging, calcium deficiency, excessive parathyroid hormone, calcitonin deficiency, active vitamin D deficiency, estrogen deficiency, insufficient exercise, etc. Factors affecting calcium metabolism are parathyroid hormone (PTH), calcitonin (CT) and 1,25-(OH)2D3, etc. Parathyroid hormone involved in calcium metabolism counteracts calcitonin secreted in C-cells, parafollicular cells of thyroid gland. As a polypeptide, calcitonin having a molecular weight of 3,500-4,000 mediates the deposition of calcium salts in bone. That is, calcitonin reduces blood calcium and magnesium, and phosphate and hydroxyproline in urine. Parathyroid hormone (PTH) is also a polypeptide having molecular weight of 8447. Parathyroid hormone activates osteoclasts, resulting in the increase of bone resorption and activity of vitamin D3 in small intestinal mucosa. So, PTH increases blood calcium and magnesium, and hydroxyproline and phosphate (PO43—) in urine. Estradiol, asteroid secreted in ovary, activates osteoblasts in bone, thereby inhibits bone resorption.
Postmenopausal women exhibit lower level of estrogen, and as a result, the level of blood calcitonin as well as 1,25-(OH)2D3 synthesis in kidney is reduced, while the level of PTH is elevated. Accordingly, productions of interleukin 6 (IL-6) and prostaglandin are promoted, resulting in the decrease of calcium absorption in small intestine and the increase of bone loss by active osteoclast mediated bone resorption. As a result, osteoporosis is developed. In general, when bone resorption outpaces bone formation, joint dysfunction, gradual vertebral malformation, minor fracture in vertebra and other regions, lowered mobility by pain (in particular lumbo-dorsal pain) and contracted kidney by kyphosis are observed.
Osteoporosis is characterized more by bone decrease in amount leading to fractures including femur fracture or vertebral fracture than by its symptoms, and has been a public health problem limiting public activities for long-term. So, 15% of causes of death of the aged are attributed to osteoporosis. Bone density is affected by genetic factors, nutrition, hormone changes, exercise and habits. Aging, insufficient exercise, low weight, smoking, low calcium diet, menopause and ovariectomy are known as major causes of osteoporosis.
In the meantime, it is known that black people exhibit lower bone resorption level than white people, meaning black people have bigger bone mass. The peak bone mass is observed between age 14 and 18, and then reduces 1% per year. In particular, bone is continuously decreased from the age of 30 in women, and is rapidly reduced after menopause by hormone change.
Osteoporosis, more or less, is inevitable in the aged, especially in postmenopausal women, so osteoporosis and its therapeutic agent have been in the center of our concern as an aging population grows in advanced countries.
The treatment of bone diseases forms approximately 130 billion dollar-market throughout the world, which is assumed to be growing further. Thus, numbers of research teams and pharmaceutical companies have invested to develop a therapeutic agent for bone diseases and an inhibitor for bone resorption.
Osteoporosis-related studies have been focused on inorganic substances in bone, specifically on calcium and phosphorus metabolism, so far. However, concrete pathogenic mechanism has not been disclosed, yet.
A therapeutic agent for osteoporosis being used today is exemplified by bisphosphonate products (alendronate, etidronate), hormone products (raloxifene), vitamin D products, calcitonin products and calcium products, etc. However, bisphosphonate products have problems of low absorption rate, troublesome administration methods and inducing esophagitis. Hormone products require life-time administration, which has possibility of carrying side effects such as breast cancer, uterine cancer, cholelithiasis and thrombosis, etc. Vitamin D products are expensive but not much effective. Calcitonin products have also problems of high costs and hard administration. Calcium products have less side effects but are limited to rather prevention than treatment.
Short-term administration of a drug is not much effective for the treatment of osteoporosis, and thus long-term administration of a drug is inevitable. Therefore, a novel agent having less side effects but more medicinal effects is required for long-term administration.
The present inventors, thus, have studied on various physiological activities of Rehmanniae Radix Preparata and Acanthopanacis Cortex. And the inventors finally completed the present invention by confirming that a herbal mixture extract of Rehmanniae Radix Preparata and Acanthopanacis Cortex has no toxicity, enhances the expression of osteoprotegerin, a protein inhibiting generation and activation of osteoclasts, and suppresses osteoclast proliferation, so that the mixture can be effectively used for the prevention and treatment of osteoporosis.